Glucose-Sensing by Neurons: its Importance and the Role of UCP2 Glucose-sensing by the brain is a well documented phenomenon with potentially important implications for the pathogenesis of type 2 diabetes. Prior electrophysiological studies have determined that subpopulations of neurons are regulated by glucose. As glucose rises, "glucose-excited" neurons depolarize and increase their firing rate. Examples of glucose-excited neurons include POMC neurons in the arcuate nucleus, MCH neurons in the lateral hypothalamus and a subgroup of neurons in the ventromedial hypothalamus (VMH). The molecular apparatus responsible for excitation by glucose is thought to have similarities to that found in pancreatic (3-cells. Specifically, neuronal oxidation of glucose and/or lactate (thelatter generated by glucose metabolism in glial cells), increases the ATP/ADP ratio. This then closes neuronal KATP channels, depolarizing the neuron which then increases its firing rate. While the phenomenon of "P-cell-like" glucose- sensing in the brain is robust, its physiologic relevance and its contribution to disease states such as type 2 diabetes, is unknown. The overall goal of these studies is to assess the role of "p-cell-like" glucose-sensing by neurons in normal physiology and in the development of type 2 diabetes. This will be accomplished through the use of genetically engineered mice. First, we will disrupt "P-cell-like" glucose-sensing in a neuron-specific fashion, through transgenic expression of a mutant KATP channel, and then determine if this adversely affects insulin / glucose homeostasis (Aim 1). Second, we will determine if uncoupling protein-2 (UCP2) negatively regulates "P-cell-like" glucose-sensing in neurons and whether this could be a cause of defective glucose-sensing in type 2 diabetes (Aim 2). Third, we will determine if absence of UCP2 in neurons, which we predict will prevent loss of glucose-sensing, improves obesity-induced impairments in insulin / glucose homeostasis (Aim 3). Studies proposed in this application could provide novel insight into the role of the brain in the pathogenesis of type 2 diabetes. Such insight could result in novel treatments for this disease.